GB2173101A

GB2173101A - Dopaminergic composition containing dihydroergocryptine

Info

Publication number: GB2173101A
Application number: GB08607848A
Authority: GB
Inventors: Stefano Poli
Original assignee: Poli Industria Chimica SpA
Current assignee: Poli Industria Chimica SpA
Priority date: 1985-04-04
Filing date: 1986-03-27
Publication date: 1986-10-08
Also published as: JPH0415767B2; IT8520234A0; DE3525390A1; GB2173101B; FR2579893B1; IT1200603B; JPS61257922A; US4673681A; FR2579893A1; GB8607848D0; DE3525390C2

Description

1

SPECIFICATION

Pharmaceutical compositions with dopaminergic activity This invention concerns pharmaceutical composi tionswith dopaminergic activity. More particularly, it relatesto a novel therapeutic use of (x-dihydroergoc ryptine for the treatment of central nervous system disorders such as Parkinson's disease, depression and cephalaigias (including migraines).

(x-Dihydroergocryptine, which is more systemati cally named 12'-hyd roxy-2'-) 1 -methyl ethyl)-5'(x-(2 methyl propyl)-9,1 0-di hyd ro-e rgota m a n-Y,W, 1 8-trione, is a known compound, derived bythe hydrogenation 80 of the 9,10-double bond of the natural alkaloid (x-ergocryptine. It is mainly used, in association with dihydroergocristine and dihydroergocornine, forthe therapy of cerebrovascular disturbances, especially in the elderly.

the capacity of dihydroergocryptine (and, generally, of other similar hydrogenated alkaloids) to bind otand D receptors at different levels both in the central and in the peripheral nervous systems is known. On the basis of pharmacological activities, the main use indicated for dihydroergocryptine, either alone or in association with other substances, has up to now been in the treatment of senile cerebrovascular insufficiency in its different manifestations. However, it has now been found that dihydroergocryptine, while still active in the cited pathologies, can advantageously be em ployed forthe treatment of pathological conditions of the Central Nervous System (CNS) such as parkinson ism, essential cephalalgias, and depressions,the etiological causes of which can be attributed to a dopaminergic lack.

The known treatments forthese conditions involve the administration of 1-DOPA orthe ergolinic deriva ties (x-bromocriptine and ergotamine (Calne D.B., Lancet 1978, 1,735 and Theohar C., Arzneirn. Forsch.

1982,32,783). These latter, however, have unfortun ate side effects; besides the dopaminergic agonistic action they induce an undesired peripheral activity which mitigates againsttheir use in a high percentage of patients. Thus, usage of bromocriptine leads to hypertension in 28% and syncope in 0.7% of cases, and vomiting in 3% of cases (Physicians'Desk Reference, 36th edit.: 1684,1982).

Surprisingly, dihydroergocryptine, while being ac tive in the treatment of the CNS pathological condi- 115 tions mentioned above, does not show any of the peripheral nervous system side effects common to the known ergolinic compounds. This phenomenon suggests that dihydroergocryptine has a selective CNS dopaminergic activity, which was quite unforeseeable 120 from what had been known upto now.

The invention may therefore be seen to relate to the use of (xdihydroergocryptine in the freatment of conditions the cause of which can be attributed to a lack of dopaminergic activity, specifically pathological 125 Central Nervous System disorders such as parkinsonism, essential cephalalgias (including migraines) and depressions. The invention may also be seen to concern pharmaceutical compositions for use in this treatment, the compositions comprising as the or an - 130 GB 2 173 101 A 1 active ingredient (x-dihydroergocryptine (ora pharmaceutically-acceptable salt thereof) in association with a suitable carrier therefor.

Accordingly, in one aspectthis invention provides the use of (x-dihydroergocryptine, ora pharmaceutically-acceptable saItthereof, in the manufacture of medicamentsfor use in the treatment of pathological central nervous system conditions attributableto a dopaminergic lack.

The (x-dihydroergocryptine is conveniently employed in the form of a pharmaceutically-acceptable salt. Typical such salts are acid addition salts of the suphonate variety, particularlythe alkanesulphonates such as the methanesulphonate (the mesylate).

(x-Dihydroergocryptine can be administered by oral, sublingual, parenteral or percutanous routes, and thereforethe medicamentto be prepared may be a pharmaceutical composition in anyform suitablefor that route chosen,the carrieremployed being in turn whatever is suitableforthe physical form of the composition. The compositions may be prepared according to the usual techniques, employing compatible and pharmaceutically-acceptable excipients and carriers. They may also contain, in association, other active principles with an activitythat is complementary, or otherwise useful. Typical compositions takethe form of capsules, pills, tablets, drops, patches fortransdermal administration, and ampouiesfor intra-muscuiaror intra-venous adminis- tration, and may include delayed action formulations allowing the prolonged administration of the active principle.

Appropriate dose rates for (x-dihydroergocryptine depend upon the condition forwhich it is adminis- tered, and may varyfrom 2 mg and lessto 20 mg and more per day, while individual doses may contain from 0.5 mg (and less) to 100 mg (and more). Expressed asthe methanesulphonate, a suitable daily dose forthetreatment of parkinsonism isfrom 1 Oto 200 mg, especially 10 to 100 mg, according to the weight and condition of the patient, whileforthe treatment of depressions and cephalaigias lower doses-for example, from 2 to 20 mg, especiallyfrom 2 to 10 mg, one to three times a day- are satisfactory.

TestResults In the treatment of Parkinson's disease dihydroergocryptine, administered asthe metha nesu 1 phonate, was found to be active in reducing tremors, akinesia and rigidity at dose levels from 1 Oto 100 mg daily, when administered alone in de novo patients.

In Table 1 belowthere are shown changes in symptomatology in 7 de novo parkinsonian patients treated atthe 40 mg per day rate.

Moreover, dihydroergocryptine, administered in parkinsonian patients alreadytreated with 1 -DOPA and bromocriptine (BCR), allowed the completewithdrawal of the BCR and the reduction of the 1 -DOPA dosage (with a subsequent clear reduction in side effects), while maintaining the same therapeutic activity level in the same patients.

In Table 2 belowthere are reported the changes of symptomatology in 7 parkinsonian patients, already treated with both BCR and 1 -DOPA, after replacement of BCR with a placebo and the subsequent introduction of dihydroergocryptine atthe 40 mg per day rate.

2 GB 2 173 101 A 2 Furthermore, dihydroergocryptine was shown to be 20 capsules, drops and ampoules, are asfoilows:active in the treatment of depression, a disease in which a dopaminergic lack is admitted. In the treatment of depressed patients, dihydroergocryptine showed a particular speed of action and tolerability higherthan any of the tricyclic antidepressants, thus leading one to adopt its use in elderly patients with depressive symptomatology.

Table 3 below shows the evolution of depressive symptomatology in 18 patients treated with dihydroergocryptine drops (1.5 to 2 mg) th ree times daily.

Chronically administered in patients with essential orvasomotorcephalaigias, dihydroergocryptine induced a 57.8% reduction in frequencyand severity of headaches, allowing a recoveryto active life and a lower consumption of antalgic agents. Formulations Byway of example only, three preferred medicaments- pharmaceutical compositions- in the form of TABLE 1

Drops mi contain:

Dihydroergocryptine methanesulphonate 200 mg propylene glycol q.s.

Ampoules Each ampoule contains:

dihydroergocryptine metha nesu 1 phonate 0.5 mg Propylene glycol 10Orng Methanesulphonic acid q.s. to pH3 Bidistilled waterq.s. to 1 m[ Capsules One capsule contains:

dihydroergocryptine methanesuiphonate 3mg Starch, lactose magnesium stearate microcrystalline cellulose q.s. to BASAL WEEKS OF TREATMENT VALUES 2 5 16 Dp- DQM 14.86k1.67 13.28':tl.gl 12.14'.tl.6'7 11.43-kl,68 10.43'1.69 patients 30.14 5'.87 28.86 5.61 26.71:t5.27 23.57- 5,57 21.71':t5.55_ 1 YRS: Webster RatinS Scale (Webster D.B., 1968 "dern Treatment 5, 217).

2 CURS: Columbia University RatinS Scale (DUVOISIN R.C., 1970 - The evalution a E.tr.pya.id.1 Disease. In 'Xcnaamine, noyaux gris centraux et syndrome de Parkinsoam; do Ajuriaggera J. (Ed.) Xasson, Paris, pp.313325).

-P<0.01 m basal values TABLE 2

BCR PLACEBO DIRYDR ERGOCRYPTINE Patients.1r..dy under treatment 19.86-k1.84 22.71k2.01 19.53:t2.23 1th BRC + I-DOPA Fts:- 30.57 6.8 37.86 6.97 30.0 7.24 P<O. 01 Y,-, placebo TABLE 3

RAXILTON RATING SCALE FOR DEPRESSION' BASAL After 7 days After 14 days After 21 clays VALUES 34.61:t1.52 24.39'1.93' 17.44:L1.80 14.50:tl.72 -<Hamilton M 1960 - S. lreurol. lteurosurg. Psychiat-2a. 56 P 0.01 7,a basal values 1. -Hamilton M_ 1960-J. Neurol. Neurosurg. Psychiat. w23,56

Claims

PiO.01 vsbasalvalues CLAIMS

1. The use of (x-dihydroergocryptine, or a pharmaceutica lly-accepta ble salt thereof, in the man ufacture of medicaments for use in the treatment of pathological central nervous system conditions attributable to a doparninergic lack.

2. A use as claimed in Claim 1, in whichthe ot-dihydroergocryptine is employed in the form of the methanesulphonate.

3. A use as claimed in either of the preceding Claims, in which the medicament takes the form of capsules, drops, patches for transderma 1 administration, orampoules for intra-muscular or intra-venous administration.

4. A use as claimed in any of the preceding Claims, in which individual doses of the medicament ......................... 10Orng contain from 0.5 to 100 mg ofthe oc-dihydroergoeryptine.

5. A use as claimed in any of the preceding Claims 60 and substantially as described herein before.

Printed in the United Kingdom for Her Majesty's Stationery Office, 8818935, 10186 18996. Published at the Patent Office, 25 Southampton Buildings, London WC2A lAY, from which copies may be obtained.